The present invention, in some embodiments thereof, relates to novel compounds, to pharmaceutical compositions containing same and to uses thereof in the treatment of neurodegenerative diseases and disorders, such as Parkinson's disease.
Parkinson's disease is an age-related disorder characterized by progressive loss of dopamine producing neurons in the substantia nigra of the midbrain, which in turn leads to progressive loss of motor functions manifested through symptoms such as tremor, rigidity and ataxia. Parkinson's disease can be treated by administration of pharmacological doses of the precursor of dopamine, L-DOPA (Marsden, Trends Neurosci. 9:512, 1986; Vinken et al., in Handbook of Clinical Neurology p. 185, Elsevier, Amsterdam, 1986). Although such treatment is effective in early stage Parkinson's patients, progressive loss of substantia nigra cells eventually leads to an inability of remaining cells to synthesize sufficient dopamine from the administered precursor and to diminishing pharmacogenic effect.
Recently, Neurologix Inc. announced interim results of a gene therapy clinical trial for patients with Parkinson's disease. The gene therapy involved transforming target brain cells with glutamic acid decarboxylase (GAD) gene to thereby increase GABA synthesis in the brain. According to the interim report (wwwdotbiologynewsdotnet/archives/2005/09/25/neurologix_announces_positive_results_of_gene_therapy_clinical_trial_in_parkinsons_diseasedothtml), treated Parkinson's disease patients exhibited statistically significant improvement in motor function and a strong trend toward improvement of activities of daily living.
Unfortunately, clinical use of GABA for treating neurodegenerative disorders is presently limited since the GABA molecule comprises hydrophilic functional groups (e.g., a free carboxylic acid group and a free amino group) and therefore does not effectively cross the blood brain barrier (BBB).
In an attempt to overcome the limitations associated with the administration of GABA to the brain, Prof. Nudelman and co-researchers, which are co-inventors of the present invention, have designed and successfully practiced a series of conjugates of psychotropic drugs and GABA. These conjugates and their advantageous use in the treatment of psychotic and/or proliferative diseases and disorders are described in detail in International Patent Application published as WO 03/026563, which is incorporated by reference as if fully set forth herein.
Accordingly, International Patent Application WO 2005/092392, by the same inventors, which is also incorporated by reference as if fully set forth herein, teach psychotropic drugs coupled to GABA.